Conventional means for delivering drugs are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, and/or the target itself. Examples of physical barriers include the skin, lipid bi-layers and various organ membranes that are relatively impermeable to certain drugs but must be traversed before reaching a target, such as the circulatory system. Chemical barriers include, but are not limited to, pH variations in the gastrointestinal (GI) tract and degrading enzymes.
These barriers are of particular significance in the design of oral delivery systems. Oral delivery of many drugs would be the route of choice for administration if not for biological, chemical, and physical barriers that prevent, restrict or reduce the passage of drugs. Among the numerous agents in this category are gallium salts.
U.S. Pat. No. 4,529,593 discloses a method of preventing or treating a disorder associate with accelerated loss of calcium from bone in a human individual by administering to the individual a pharmaceutically acceptable gallium compound, such as gallium nitrate.
U.S. Pat. No. 4,704,277 discloses a method of increasing bone growth, decreasing hydroxyapatite solubility, increasing the size and/or the perfection of hydroxyapatite crystals in bone, and/or increasing the tensile strength of bone by administering to an individual a pharmaceutically acceptable gallium compound, such as gallium nitrate.
Gallium nitrate is currently marketed as Ganite™, an intravenous injection, for the treatment of clearly symptomatic cancer-related hypercalcemia that has not responded to adequate hydration. Gallium nitrate is not currently available as an oral formulation due to its poor oral bioavailability. According to the FDA approved labeling for Ganite™, gallium nitrate exerts a hypocalcemic effect by inhibiting calcium resorption from bone, possibly by reducing increased bone turnover.
Additionally, according to the FDA approved labeling for Ganite™ hypercalcemia is a common problem in hospitalized patients with malignancy. It may affect 10-20% of patients with cancer. Different types of malignancy seem to vary in their propensity to cause hypercalcemia. A higher incidence of hypercalcemia has been observed in patients with non-small cell lung cancer, breast cancer, multiple myeloma, kidney cancer, and cancer of head and neck. Hypercalcemia of malignancy seems to result from an imbalance between the net resorption of bone and urinary excretion of calcium. Patients with extensive osteolytic bone metastases frequently develop hypercalcemia. This type of hypercalcemia is common with primary breast cancer. Some of these patients have been reported to have increased renal tubular calcium resorption. Breast cancer cells have been reported to produce several potential bone-resorbing factors which stimulate the local osteoclast activity. Humoral hypercalcemia is common with the solid tumors of the lung, head and neck, kidney, and ovaries. Systemic factors (e.g., PTH-rP) produced either by the tumor or host cells have been implicated for the altered calcium fluxes between the extracellular fluid, the kidney, and the skeleton. About 30% of patients with myeloma develop hypercalcemia associated with extensive osteolytic lesions and impaired glomerular filtration. Myeloma cells have been reported to produce local factors that stimulate adjacent osteoclasts. Hypercalcemia may produce a spectrum of signs and symptoms including: anorexia, lethargy, fatigue, nausea, vomiting, constipation, polyuria, dehydration, renal insufficiency, impaired mental status, coma, EKG abnormalities and cardiac arrest.
One type of hypercalcemia, “Non-PTH-Mediated Hypercalcemia”, is theorized to result from an increase in osteoclastic activity. While malignant disorders are a common cause of this type of hypercalcemia, it may also be due to other causes. Granulomatous disorders with high levels of calcitriol may be found in patients with sarcoidosis, berylliosis, tuberculosis, leprosy, coccidioidomycosis, and histoplasmosis. Iatrogenic disorders of calcium levels may increase secondary to the ingestion of many medications (e.g. thiazide diuretics, calcium carbonate, hypervitaminosis D, hypervitaminosis A, lithium, milk-alkali syndrome and thephylline toxicity). Chronic renal failure, post transplant states and hemodialysis may also cause hypercalcemia.
Hypercalcemia may also result from Primary Hyperparathyroidiam. Plasma calcium is maintained within the reference range by a complex interplay of 3 major hormones, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (ie, calcitriol), and calcitonin. These 3 hormones act primarily at bone, kidney, and small intestine sites to maintain appropriate calcium levels. In most primary hyperparathyroidism cases, the calcium elevation is caused by increased intestinal calcium absorption. This is mediated by the PTH-induced calcitriol synthesis that enhances calcium absorption. The increase in serum calcium results in an increase in calcium filtration at the kidney. Because of PTH-mediated absorption of calcium at the distal tubule, less calcium is excreted than might be expected. Generally, in PTH-mediated hypercalcemia, bones do not play an active role because most of the PTH-mediated osteoclast activity that breaks down bone is offset by hypercalcemic-induced bone deposition.
International Publication No. WO 2006/072070 describes pharmaceutical formulations containing a pharmaceutically acceptable gallium salt (such as gallium nitrate), a delivery agent, and optionally, one or more chemotherapeutic agents and/or adjunctive chemotherapeutic agents.
A goal of treatment is to stabilize and reduce the calcium level, increase urinary calcium excretion, inhibit osteoclast activity in the bone, and treat underlying causes when possible.
There is a need for improved oral delivery systems for gallium salts which provide sufficient bioavailability to treat hypercalcemia.